Nu-(arylcarbamoyl)- and nu-(arylthiocarbamoyl)-glucosamines



United States Patent M 3,155,599 N-(ARYLCARBAMGYL)- ALJD N-(ARYLTHIQ- CAREAMQYH-GLUCQEAMENES Charles Morel, Arlesheim, Easel-Land, Switzerland, as-

signor to Geigy Qhemical Corporation, Ardsley, NFL, a corporation of Delaware No Drawing. Filed Feb. 25, 1963, Ser. No, 269,378 (Ilaims priority, application Switzerland, lune 21, 1969, 7,917/6tl 4 Gaims. (Cl. 26211) This application is a continuation-in-part of my copending application Serial No. 118,242, filed June 20, 1961 (abandoned since the filing of the present application).

The present invention relates to new derivatives of glucosamine and more particularly to new N-arylcarbamylglucosarnines which have valuable pharmacological properties.

The novel compounds are characterized by an N-phenylurea or N-phenylthiourea moiety with from one to two substituents in the benzene nucleus as defined below, and by a D-glucosyl radical at the second nitrogen atom of the urea or thiourea moiety.

Hitherto, phenylureas substituted with l-desoxy sugar alcohol radicals such as the sorbityl radical and cyclic urethanes thereof have been used as herbicidal compositions, as insecticides, solvents, agents for supplying rewetting properties to wet strength resins in the paper industry, and as depressants of the surface tension of water, foam, stabilizers, and detergents. The cyclic sorbitylurethanes have also been recommended in agriculture on account of their antibacterial systemic activity and fungicidal activity coupled with their lack of phytotoxicity.

It has now been discovered that, surprisingly, the abovementioned new compounds which are substituted phenylureas and phenylthioureas containing no l-desoxy sugar alcohol, i.e., no sorbityl radical, but instead the radical of a reducing sugar, and more particularly a D-glucosyl radical, of the formula wherein R represents a member selected from the group consisting of halogen, lower alkyl, trifluoromethyl and nitro,

R represents a member selected from the group consisting of hydrogen, halogen and lower alkyl, and

X represents a member selected from the group consist ing of oxygen and sulfur,

possess analgetic, antiphlogistic, antipyretic and serotonin-antagonistic activity and are therapeutically useful in the treatment of infiammations of the respiratory system on oral or parenteral administration.

Lower in the above definition of Formula I means mm 1 to 5 carbon atoms, unless stated otherwise.

In the compounds of the Formula 1, R is, for example, chlorine, fluorine, bromine, the nitro, trifiuoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isooutyl, tertiary butyl, n-amyl, isoamyl, diethylmethyl, tertiary amyl. R is, for example, hydrogen or one of the substituents given for R, with the exception of the nitro group and the trifluoromethyl group. Of enhanced value are compounds wherein R, is chlorine, the methyl group or the methoxy group and R is hydrogen, chlorine or the methyl group.

The compounds of Formula I are obtained by reacting a.- or ,8-1,3,4,6-tetra-acetyl-D-pyranoglucosamine with a 3,l53,5@ Patented Nov. 24., l9fi4= compound of the general formula R9 (II) wherein R R and X have the meanings given above, and converting the reaction product of the formula wherein Ac is the acetyl radical and R R and X have the meanings given above, by treatment with ammonia in a lower alkanol, preferably with 1 to 3 carbon atoms, into the corresponding compound of the Formula I.

The reaction of 0cor B-1,3,4,G-tetra-acetyl-D-pyranoglucosamine with a compound of the Formula II is performed advantageous in a suitable inert organic solvent such as, e.g., benzene, toluene, methylene chloride or dioxan; the reaction is performed at elevated temperature, e.g., at the boiling temperature of the solvent. The splitting olif of the acetyl groups in the compounds obtained of the Formula ill to convert them into the compounds of the Formula I is performed, for example, by treatment with methanolic or ethanolic ammonia solution at low temperatures, e.g., at room temperature (20 C.).

In the compounds of the Formula 1, R is, for example, chlorine, fluorine, bromine, nitro, triiiuoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. hutyl, n-amyl, isoamyl, diethylmethyl, tert. amyl.

R is, for example, hydrogen, or one of the substituents given for R with the exception of the nitro group and the trifiuoromethyl group.

Of particular value are compounds wherein R is chlorine, the methyl group or the methoxy group, R is hydrogen, chlorine or the methyl group, and X is sulfur.

R in Formulas I, II and ill can also be a lower alkoxy group, in particular the methoxy group mentioned supra, when X is oxygen, while, When X is sulfur, the reaction proceeds directly to the formation of compounds having a tetrahydroimidazole ring fused with glucosyl ring to form a D-glucopyrano moiety.

The following examples further illustrate the preparation of compounds of Formula 1. Parts are given as parts by weight; their relationship to parts by volume is as that of grams to cubic centimeters. The temperatures are in degrees centigrade.

EXAMPLE 1 (a) 3.6 parts of ,8- 1,3,4,6 -tetra-acetyl-D-pyran0glucosamine (Berichte 64B, 975 (1931)) and 2.1 parts of 3,4-dichlorophenyl isocyanate in parts by volume of anhydrous benzene are boiled under reflux for 2 hours While excluding moisture. After cooling, the fi-1,3,4,6- tetra-acetyl-N- 3,4-dichlorophenyl-carbamoyl) -D-pyranoglucosamine is filtered off, washed with benzene and recrystallized from alcohol. M.P. 190191, [a] +365", c.=1.02 in dimethyl formamide.

(b) 5 parts of the above product are dissolved in 50 parts by volume of anhydrous methanol and, at 0, parts by volume of a solution, saturated at 0, of ammonia in anhydrous methanol are added. The reaction solution is left to stand for 30 minutes at 0 and then for 3 hours at room temperature, whereupon it is evaporated to dryness in vacuo. The residue is recrystallized from ethanol whereupon N-(3,4-dichlorophenyl-carbamoyl)-D-glucosamine is obtained; Ml. 171-172", [a] +32.4, c.=1 in dimethyl formamide.

In, 0A0

anol and, at 400 parts by volume of a solution, saturated at 0, of ammonia in anhydrous methanol are added. The reaction solution is left for 2 hours at 0 and then for 4 hours at room temperature and afterwards evaporated to dryness in vacuo. The residue is dissolved as far as possible with 30 parts of hot Water and, after filtering, the aqueous solution is left to crystallize. The N-(3,4-dirnethylphenylthiocarbamoyl)-D-glucosamine melts at 188-189", [a] +6.3", c.=1 in dimethyl formarnide.

The following compounds, for example, are also obtained analogously to the above examples from the corresponding starting materials:

Table I Intermediate of Formula III (limited to -compounds) CHg-OAO 13/41 0 0A0 A00 OAc H H T Expl. X M.P., When crystal- T C.) [a] 0.111

No. X degrees lizedfrom- D DMF R; (degrees) s (31 3a @431 s 134-135 Ether 21 +100 1.05

42. @421 0 200-210 Ethanol 24 +3214 1.02

5a Q-m s 100-101 Methanol 23 +215 1 6a N01 0 220-222 Ethanol 21 +400 0 0.08

721 --om o 200201 d0 2t +3810 1.03

8a -CH: s 158-159 Methanol 21 +35.0 101 9a 0-0011; 0 203-201 Ethanol +352 1.01

11a Q s F137 d0 25 +111 1 I 12a Q-OHQ 0 210-211 (1O 25 +301 1 01 I 13a.-.. Q 0 202-203 -.--do 25 +312 1 01 1 14a Q s 152-152 Ether 24 +25.s 0.98

*D MF=dimethyl formamide.

Table II Compounds of Formula I:

CHzOH 11/11 v 11, OH H OH H EILCLW R1 T[ 1 a Expl. X M.P., When crystal- '1 C.) D c. in No. R degrees lized from (degrees) DMF 3b Q-Ol s 180182 1101131101 23 -7.3 1. 01

5b o1 s 144-147 Ethanol/ether-.- 22 +30 1.08

6b Q-NO: 0 153-155 Ethanol +177 1 7b OH= 0 179-101 Ethanol/water 23 +412 1. 03

8b -0Ha s 154-157 11011111101; 22 +102 1. 01

0b Q-oon; 0 muss Ethanol/ether 23 +13.1 1.01

10b Q 0 1111102 Ethanol/wetter" 23 +55.s 0.09

11b s 204-206 Water 24 -21.0 1.07

12b OH3 0 184-180 Ethanol +47.0 1.1

14b 01 102-104 Ethanol/water 27 -13.5 1.01

1 In ethanol. 2 DMF/HzO 9:1.

What I claim is: in which A compound of the formula R represents a member selected from the group consist- ES ing of halogen, lower alkyl, trifluoromethyl and nitro, 7 and, in the case of X being oxygen, also lower alkoxy, I OH R represents a member selected from the group consist- HO L R1 ing of hydrogen, halogen and lower alkyl, and

H X represents a member selected from the group consisting R2 of oxygen and sulfur.

2. N (3,4 dichloropheiylthiocarbamoyl)-D-g1ucosa- References Ciied in 21c file of this patent mine. UNITED STATES PATENTS 3. N-(3,4-dimethylphenylcarbamoyl)-D-glucosamine. 7 alZ g Dec. 13, 1938 4. N-(4-chloropheny1carbamoy1)-D-glucosamine. 5 2612497 Mail-er Sept 1952 2,663,729 Searle et a1 D60. 22, 1953 

1. A COMPOUND OF THE FORMULA 